Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.
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PMID:Protein-truncating mutations in ASPM cause variable reduction in brain size. 1457 46

Primary microcephaly (microcephalia vera) is a developmental abnormality resulting in a small brain, with mental retardation. It is usually transmitted as an autosomal recessive trait, and six loci have been reported to date. We analyzed a translocation breakpoint previously reported in a patient with apparently sporadic primary microcephaly, at 1q31, where locus MCPH5 maps. The patient was lost to follow-up, and we sampled a maternal aunt who carried the familial translocation. FISH analyses showed that the insert of BAC clone RP11-32D17 spanned the breakpoint. The breakpoint was further located within a fragment of this insert corresponding to intron 17 of the ASPM gene, resulting in a predicted transcript truncated of more than half of its coding sequence. It is very likely that the proband carried a second ASPM mutation in trans, but he was not available for sampling and hence we could not confirm this hypothesis. Our observation adds to the mutation spectrum of ASPM in primary microcephaly, and is to our knowledge the second example of a constitutional, reciprocal translocation responsible for a bona fide autosomal recessive phenotype.
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PMID:A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly. 1499 85

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.
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PMID:Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. 1580 41

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that causes reduction in brain size. Individuals affected with the disorder show a small but architecturally normal cerebral cortex and are associated with mental retardation of mild-to severe form. MCPH is genetically heterogeneous with six loci, and four genes have been identified so far. Homozygous mutations in the ASPM gene, located at MCPH5 locus on chromosome 1q31, are the most common cause of MCPH particularly in the Pakistani population. In the present study, we have ascertained ten Pakistani and one Kashmiri family with primary microcephaly. We screened for potential mutations of the ASPM gene in seven consanguineous families (six Pakistani and one Kashmiri) linked to MCPH5 locus. Two previously reported (8508delGA, W1326X) and four novel sequence variants (Y1712X, I1717X, Y3353X, R3244X) were detected and all were predicted to be protein truncating. The degree of mental retardation in the affected individuals of the seven families varied from mild to moderate, and was not dependent on the location of mutations in the ASPM gene.
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PMID:Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly. 1784 85

Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (<or=4 SD) and mental retardation without any other neurological manifestation. Of the four identified MCPH genes, homozygous truncating mutations in ASPM (MCPH5) account for >50% of all reported families. In spite of the high frequency of MCPH in Pakistan only one case of compound heterozygosity for mutations in ASPM has been reported yet. In this large MCPH study we ascertained 37 families including 319 persons (140 patients). Haplotype analysis of eight STS markers suggested linkage by homozygosity in 20 families, and re-analysis of single sib ships in the remaining families demonstrated possible compound heterozygosity in two families. Direct sequencing indeed confirmed compound heterozygosity in two and homozygous mutations in 20 families, respectively, showing that up to 10% of families with MCPH caused by ASPM are compound heterozygous. In total we identified 16 different nonsense or frameshift mutations of which 12 were novel thereby increasing the number of mutations in ASPM significantly from 35 to 47. We found no correlation between the severity of the condition and the site of truncation. We suggest that the high frequency of compound heterozygosity observed in this study is taken into consideration as part of future genetic testing and counseling in Pakistani MCPH families.
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PMID:Compound heterozygous ASPM mutations in Pakistani MCPH families. 1935 28